Research projects

This project aims to understand the molecular mechanisms involved in the production and release of exosomes during cellular stress, and more specifically during conditions of metabolic stress and hypoxia of adipocytes. A relevant aspect that is intended to be analyzed in this regard is the contribution of some key autophagy proteins.

Results obtained: 

1. Impact of hypoxia on exosome formation. HEK293 cells underwent hypoxia during different times, and the abundance of exosomes was analyzed. Exosomes accumulated over time under normal conditions, and exposure to hypoxia increased the number of particles released which paralleled a greater abundance of the exosomal marker CD81. These results support the view that hypoxia accelerates the formation of exosomes. In addition, the genetic blockade of HIF1a activity does not prevent the accelerated exosome formation in hypoxia, which rules out its participation in this process.

2. Role of TP53INP2 protein in adipogenesis and impact on exosome formation. TP53INP2 protein activates the formation of autophagosomes by binding to ATG8 proteins, and their genetic elimination reduces although it does not cancel this activity. TP53INP2 deficiency increases adipogenic differentiation and induces a gain in adiposity in mice. At the cellular level, TP53INP2 promotes the sequestration of the GSK3β regulatory protein in multivesicular bodies (MVB) through a process that involves autophagy and the participation of ESCRT complexes of endosomal traffic. Thus, TP53INP2 stabilizes β-catenin, which in turn triggers the inhibition of adipogenesis. The genetic manipulation of TP53INP2 also promotes changes in the production of exosomes in different cells. This suggests that the TP53INP2 protein is a new positive modulator of exosome formation and release.